It has been reported that 3–4 million adults in the United States have congestive heart failure (abbreviated “CHF” herein); and the incidence of CHF is increasing (see, e.g., Baughman, K., Cardiology Clinics 13: 27–34, 1995). Annually in US hospitals, CHF is the most frequent non-elective admission and the discharge diagnosis for 500,000 patients. Once symptoms of heart failure are moderately severe, the prognosis is worse than most cancers in that 50% of such patients are dead within 2 years (Braunwald, E. (ed), In: Heart Disease, W. B. Saunders, Philadelphia, page 471–485, 1988). Although medical therapy can initially attenuate the symptoms of heart failure (edema, breathlessness, fluid in the lungs), and in some cases prolong life, the prognosis in this disease, even with medical treatment, is grim (see, e.g., Baughman, K., Cardiology Clinics 13: 27–34, 1995).
CHF is defined as abnormal heart function resulting in inadequate cardiac output for metabolic needs (Braunwald, E. (ed), In: Heart Disease, W. B. Saunders, Philadelphia, page 426, 1988). Symptoms include breathlessness, fatigue, weakness, leg swelling, and exercise intolerance. On physical examination, patients with heart failure tend to have elevations in heart and respiratory rates, rates (an indication of fluid in the lungs), edema, jugular venous distension, and, in general, enlarged hearts. The most common cause of CHF is atherosclerosis which causes blockages in the blood vessels (coronary arteries) that provide blood flow to the heart muscle. Ultimately such blockages may cause myocardial infarction (death of heart muscle) with subsequent decline in heart function and resultant heart failure. Other causes of CHF include valvular heart disease, hypertension, viral infections of the heart, alcohol, and diabetes. Some cases of heart failure occur without clear etiology and are called idiopathic.
CHF is also typically accompanied by alterations in one or more aspects of beta-adrenergic neurohumoral function; see, e.g., Bristow M R, et al., N Engl J Med 307:205–211, 1982; Bristow M R, et al., Circ Res 59:297–309, 1986; Ungerer M, et al., Circulation 87: 454–461, 1993; Feldman A M, et al., J Clin Invest 82:189–197, 1988; Bristow M R, et al., J Clin Invest 92: 2737–2745, 1993; Calderone A, et al., Circ Res 69:332–343. 1991; Marzo K P, et al., Circ Res 69:1546–1556, 1991; Liang C-S, et al., J Clin Invest 84: 1267–1275, 1989; Roth D A, et al., J Clin Invest 91: 939–949, 1993; Hadcock J R and Malbon C C: Proc Natl Acad Sci 85:5021–5025, 1988; Hadcock J R, et al., J Biol Chem 264: 19928–19933, 1989; Mahan, et al., Proc Natl Acad Sci USA 82:129–133, 1985; Hammond H K, et al., Circulation 85:269–280, 1992; Neumann J, et al., Lancet 2: 936–937, 1988; Urasawa K, et al., In: G Proteins: Signal Transduction and Disease, Academic Press, London. 44–85, 1992; Bohm M, Mol Cell Biochem, 147: 147–160, 1995; Eschenhage T, et al., Z Kardiol, 81 (Suppl 4): 33–40, 1992; and Yamamoto J, et al., J Mol Cell, 26: 617–626, 1994. See also the numerous additional references regarding various adenylylcyclase enzymes by, e.g., Fujita M et al., Circulation, 90: (No. 4 Part 2), 1994; Yoshimura M et al., Proc Natl Acad Sci USA, 89:6716–6720, 1992, which is the basis for GenBank entry GI 191690; Krupinski J et al., J Biol Chem, 267:24858–24862, 1992; Ishikawa Y et al., J Biol Chem, 267:13553–13557, 1992; Ishikawa Y et al., J. Clin Invest, 93:2224–2229, 1994; Katsushika S et al., Proc Natl Acad Sci USA, 89:8774–8778, 1992; Wallach J et al., FEBS Lett, 338:257–263, 1994; Watson P A et al., J Biol Chem, 269:28893–28898, 1994; Manolopoulos V G et al., Biochem Biophys Res Commun, 208:323–331, 1995; Yu H J et al., FEBS Lett, 374:89–94, 1995; and Chen Z et al., J Biol Chem, 270:27525–27530, 1995.
As a result of these studies and others, efforts to treat CHF have focused on the administration of pharmacological agents, such as catecholamines and other beta-adrenergic agonists, as means of stimulating beta-adrenergic responses in dysfunctional hearts. Such therapeutic approaches have been only partly successful. Furthermore, long-term exposure to catecholamines can be detrimental. In particular, the heart tends to become less responsive to beta-adrenergic stimulation, and such unresponsiveness is typically associated with high levels of catecholamines in plasma, a factor generally linked to a poor prognosis.
Present treatments for CHF include pharmacological therapies, coronary revascularization procedures (e.g. coronary artery bypass surgery and angioplasty), and heart transplantation. Pharmacological therapies have been directed toward increasing the force of contraction of the heart (by using inotropic agents such as digitalis and beta-adrenergic receptor agonists), reducing fluid accumulation in the lungs and elsewhere (by using diuretics), and reducing the work of the heart (by using agents that decrease systemic vascular resistance such as angiotensin converting enzyme inhibitors). Beta-adrenergic receptor antagonists have also been tested. While such pharmacological agents can improve symptoms, and potentially prolong life, the prognosis in most cases remains dismal.
Some patients with heart failure due tot associated coronary artery disease can benefit, at least temporarily, by revascularization procedures such as coronary artery bypass surgery and angioplasty. Such procedures are of potential benefit when the heart muscle is not dead but may be dysfunctional because of inadequate blood flow. If normal coronary blood flow is restored, viable dysfunctional myocardium may contract more normally, and heart function may improve. However, revascularization rarely restores cardiac function to normal or near-normal levels in patients with CHF, even though mild improvements are sometimes noted.
Finally, heart transplantation can be a suitable option for patients who have no other confounding diseases and are relatively young, but this is an option for only a small number of patients with heart failure, and only at great expense. In summary, CHF has a very poor prognosis and responds poorly to current therapies.
Further complicating the physiological conditions associated with CHF, are various natural adaptations that tend to occur in patients with dysfunctional hearts. Although these natural responses can initially improve heart function, they ultimately result in problems that can exacerbate CHF, confound treatment, and have adverse effects on survival. There are three such adaptive responses commonly observed in CHF: (i) volume retention induced by changes in sodium reabsorption, which expands plasma volume and initially improves cardiac output; (ii) cardiac enlargement (from dilation and hypertrophy) which can increase stroke volume while maintaining relatively normal wall tension; and (iii) increased norepinephrine release from adrenergic nerve terminals impinging on the heart which, by interacting with cardiac beta-adrenergic receptors, tends to increase heart rate and force of contraction, thereby increasing cardiac output. However, each of these three natural adaptations tends ultimately to fail for various reasons. In particular, fluid retention tends to result in edema and retained fluid in the lungs that impairs breathing; heart enlargement can lead to deleterious left ventricular remodeling with subsequent severe dilation and increased wall tension, thus exacerbating CHF; and long-term exposure of the heart to norepinephrine tends to make the heart unresponsive to adrenergic stimulation and is linked with poor prognosis.
Controlled use of pharmacological agents, such as beta-adrenergic agonists and other modulatory drugs, thus remains one of the major forms of treatment despite its shortfalls, including its potentially adverse effect on survival. Researchers who have analyzed and in some cases cloned DNA sequences encoding individual components involved in the beta-adrenergic receptor pathway have proposed using such components to identify new classes of drugs that might prove more useful in treating CHF. For example, Ishikawa et al. cloned DNA encoding two different isoforms of adenylylcyclase (ACV and ACVI) that are known to be predominant in mammalian cardiac tissue, and proposed using the DNA and/or recombinant protein to identify new classes of drugs that might stimulate adrenergic pathways (See, e.g., American Cyanamid, WO 93/05061, 18 Mar. 1993, and EP 0 529 662, 3 Mar. 1993; and Ishikawa U.S. Pat. No. 5,334,521, issued 2 Aug. 1994). In other reports in which cloned components of the adrenergic stimulation pathway were investigated, the authors generated transgenic mice overexpressing certain components (including cardiac beta2-adrenergic receptors. Gs alpha and G-protein receptor kinase inhibitors) and obtained some data suggesting that beta-adrenergic stimulation may be enhanced in transgenic mice (see, e.g., Gaudin C, et al., J Clin Invest 95: 1676–1683, 1995; Koch W J, et al., Science 268: 1350–1353, 1995; and Bond R A, et al., Nature 364: 272–276, 1995). None of these reports showed that cardiac function could be effectively restored in animals with heart failure, nor did they show that adrenergic responsiveness could be enhanced in large animal models that would be considered predictive of success in treating CHF in humans.
Indeed, reflecting on the observed difficulties associated with the clinical use of beta-adrenergic agonists (such as dopamine and dobutamine), a recent review concluded that beta-adrenergic stimulation appears to be harmful; and that, on the contrary, beta-receptor “blockers” or antagonists may be more useful for improving morbidity and mortality rates (see, e.g., Baughman, K., Cardiology Clinics 13: 27–34, 1995). While some agents may improve symptoms, the prognosis for patients receiving such pharmacological agents remains dismal.
The invention described and claimed herein addresses and overcomes these and other problems associated with the prior art by providing techniques by which cardiac function can be effectively enhanced in vivo without the administration of beta-adrenergic-agonist drugs.